EP0317427B1 - Substituierte Derivate von 20,21-Dinoreburnamenin, Verfahren zur Herstellung und so hergestellte Zwischenprodukte, ihre Verwendung als Arzneimittel und diese enthaltende pharmazeutische Zusammenstellungen - Google Patents

Substituierte Derivate von 20,21-Dinoreburnamenin, Verfahren zur Herstellung und so hergestellte Zwischenprodukte, ihre Verwendung als Arzneimittel und diese enthaltende pharmazeutische Zusammenstellungen Download PDF

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Publication number
EP0317427B1
EP0317427B1 EP88402872A EP88402872A EP0317427B1 EP 0317427 B1 EP0317427 B1 EP 0317427B1 EP 88402872 A EP88402872 A EP 88402872A EP 88402872 A EP88402872 A EP 88402872A EP 0317427 B1 EP0317427 B1 EP 0317427B1
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Prior art keywords
formula
16alpha
product
methyl
radical
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French (fr)
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EP0317427A1 (de
Inventor
Nurgün Aktogu
François Clémence
Claude Oberlander
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Aventis Pharma SA
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Roussel Uclaf SA
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • a very particular subject of the invention is the compounds of formula (I) characterized in that the hydrogen atom in position 3 and the hydrogen atom in position 16 are trans, in all the isomeric forms which are racemic or optically active as well as addition salts with mineral or organic acids and those characterized in that the grouping represents either is in all possible racemic or optically active isomeric forms, as well as addition salts with mineral or organic acids.
  • the invention also relates to a process for the preparation of the compounds of formula (I) characterized in that a compound of formula (II) is reduced: in which R1, R2 and R3 have the meanings already indicated to obtain a compound of formula (I A ) corresponding to a product of formula (I) in which: represented said compound of formula (I A ) being, if desired, dehydrated to obtain a corresponding compound of formula (I B ), representing a compound of formula (I) in which: represented said compound of formula (I B ) being, if desired, reduced to the corresponding compound of formula (I C ) representing a compound of formula (I) in which: represented and treats, if desired, all the products of formula (I) obtained with a mineral or organic acid to form the salt.
  • the medicaments which are the subject of the invention can be used in the treatment of cerebral insufficiencies of anoxic or ischemic origin in memory and attention disorders. They can also be used as anti-depressants.
  • the invention extends to pharmaceutical compositions containing, as active principle, the medicaments defined above.
  • Example 2 [( ⁇ ) (16alpha)] 11-chloro 20,21-dinoreburnaminine and its neutral fumarate .
  • Example 25 Neutral fumarate of [( ⁇ ) (16alpha)] 14,15-dihydro 11-methoxy 20,21-dinoreburnaminine
  • Example 30 ( ⁇ ) 10-methoxy 20,21-dinoreburnaminine hemifumarate
  • Example 36 Neutral fumarate of [( ⁇ ) (16alpha)] 9,10,11-trimethoxy 20,21-dinoreburnaminine
  • Example 41 [( ⁇ ) 16alpha)] 9-nitro 20,21-dinoreburnaminine acid maleate.
  • Example 43 [(16alpha) ( ⁇ )] N, N-dimethyl 20,21-dinoreburnamin-11-amine maleate.
  • Example 45 [(16alpha) ( ⁇ )] acid maleate N-20,21-dinoreburnamenin-11-yl) acetamide.
  • Example 46 [(16alpha) ( ⁇ )] acid maleate 20,21-dinoreburnaminenin-11-amine.
  • Example 49 [( ⁇ ) (16alpha)] 14,15-dihydro 11-ethyl 20,21-dinoreburnamenin-14-ol.
  • Example 50 [( ⁇ ) (16alpha)] 11-ethyl 20,21-dinoreburnaminine acid maleate.
  • Example 51 [(16alpha) ( ⁇ )] 14.15-dihydro 11-ethoxy 20.21 dinoreburnamzier-14-ol.
  • Example 53 [(16alpha) ( ⁇ )] 14.15-dihydro 11-hydroxy 20.21-dinoreburnaminenin-14-ol.
  • Example 55 (3alpha) 11-methyl 20,21-dinoreburnaminine maleate.
  • Stage B (3alpha) 11-methyl 20,21-dinoreburnaminine.
  • Stage C (3alpha) 11-methyl 20,21-dinoreburnaminine maleate.
  • Stage A [(16alpha) ( ⁇ )] 11-ethenyl 20,21-dinoreburnamenin-14 (15H) -one.
  • Stage B [(16alpha) ( ⁇ )] 11-ethyl 20,21-dinoreburnaminenin-14 (15H) -one.
  • the incubated suspensions are filtered on Whatman GF / C and the filters are washed with three times 5 ml of NaKPO4 buffer pH 7.4 at 0 ⁇ C.
  • the radioactivity of the filters is measured by liquid scintillation.
  • the test is carried out in the male rat Spragne Dawley (Charles River) anesthetized with ethyl ether, immobilized (tubecarine 1 mg / Kg IV) and artificially ventilated in air.
  • the electrocorticogram (ECoG) and blood pressure are recorded.
  • the rectal temperature is maintained around 36 ⁇ C and the capnia between 35 and 40 torr.
  • the products are administered at a dose of 10 mg / kg by IV route in a volume of 1 ml / Kg 3 min before the asphyxia obtained by stopping artificial respiration.
  • the latency time of disappearance of the ECoG is measured.
  • mice consists in measuring over a maximum duration of 3 minutes the survival time of mice placed in a 2-liter enclosure in which a depression of 600 mmHg is produced. Mice have been fasting for 6 hours. The products are administered at a dose of 10 mg / kg i.p. in a volume of 0.2 ml / 10 g 60 minutes before the test.
  • the increase in the survival time, expressed as a percentage, of the treated animals compared to the control animals, subject to the same conditions, is noted.
  • Rats are placed individually in the lighted compartment of a two-compartment box, the other being dark. They spontaneously take refuge in the dark compartment and as soon as they enter, the rats receive an electric shock (1mA / 5sec) through the mesh floor.
  • the animals are then divided into 3 groups: the 1st group (control) does not undergo any other manipulation.
  • the electric shock is immediately followed by the application of an amnesic electroshock (60mA, 0.6ms, 0.6s) electroshock control group).
  • the 3rd group is identical to the 2nd, but the electroshock is immediately followed by the administration of the compound to be tested (treated group).
  • the method used consists in creating a memory deficit in the rat, by lesion of the septohippocampal cholinergic system and, in researching whether the tested product is likely to reverse this deficit.
  • this deficit is evaluated in a spontaneous alternation behavior; the injured animal has alternation performances close to 50%, because it makes its choices by chance.
  • Each experiment includes a control-vehicle group, an injured-vehicle group and one or two injured groups receiving the test product.
  • each rat is subjected to one session per day, comprising four tests themselves divided into two parts: a forced choice and a free choice.
  • the product is administered intraperitoneally (ip) 30 minutes before each session.
  • Example 10 reverses the memory deficit caused by the cholinergic septal lesion in a range of doses from 1 to 10 mg / kg i.p.
  • the compound is administered i.p. successively 24, 5 and 1/2 hour before the test.
  • the first administration takes place immediately after the initial swimming test, just before replacing the animals in their breeding box.
  • the means of the treated groups are compared with those of the control group by the Dunnett test.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Cardiology (AREA)
  • Psychiatry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Silicates, Zeolites, And Molecular Sieves (AREA)
  • Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
  • Peptides Or Proteins (AREA)
  • Indole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Claims (13)

  1. Verfahren zur Herstellung von Verbindungen der Formel (I):
    Figure imgb0224
     in der R₁, R₂ und R₃, die gleich oder verschieden sein können, ein Wasserstoffatom, ein Halogenatom, einen Alkyl- oder Alkoxyrest mit 1 bis 5 Kohlenstoffatomen, einen Hydroxy-, Trifluormethyl-, Nitro-, Amino-, Alkylamino-, Dialkylaminorest, in dem der Alkylrest 1 bis 5 Kohlenstoffatome einschließt, einen Acylaminorest, in dem der Acylrest ein Rest einer aliphatischen Säure mit bis zu 6 Kohlenstoffatomen ist, darstellen, wobei R₁, R₂ und R₃ nicht gleichzeitig ein Wasserstoffatom darstellen können, und in der die Gruppe:
    Figure imgb0225
     entweder für:
    Figure imgb0226
     oder:
    Figure imgb0227
     oder auch:
    Figure imgb0228
     steht, wobei die Produkte der Formel (I) in allen möglichen racemischen oder optisch aktiven isomeren Formen vorliegen, sowie der Additionssalze der Produkte der Formel (I) mit Mineral- oder organischen Säuren,
    dadurch gekennzeichnet, daß man eine Verbindung der Formel (II):
    Figure imgb0229
     in der R₁, R₂ und R₃ die bereits angegebenen Bedeutungen aufweisen, reduziert, um eine Verbindung der Formel (IA) zu erhalten, welche einem Produkt der Formel (I) entspricht, in der:
    Figure imgb0230
     für
    Figure imgb0231
     steht, wobei die Verbindung der Formel (IA), falls gewünscht, dehydratisiert wird, um eine der Formel (IB) entsprechende Verbindung zu erhalten, welche eine Verbindung der Formel (I) darstellt, in der
    Figure imgb0232
     für
    Figure imgb0233
     steht, wobei die Verbindung der Formel (IB), falls gewünscht, zu einer der Formel (IC) entsprechenden Verbindung reduziert wird, welche eine Verbindung der Formel (I) darstellt, in der:
    Figure imgb0234
     für
    Figure imgb0235
     steht,
    und, falls gewünscht, die erhaltenen Produkte der Formel (I) mit einer Mineral- oder organischen Säure behandelt, um daraus das Salz zu bilden.
  2. Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, daß man zu Beginn ein Produkt der Formel (II), in der R₁, R₂ und R₃, die gleich oder verschieden sein können, ein Wasserstoffatom oder einen Methyl-, Ethyl-, Methoxy- oder Ethoxyrest, ein Chloratom, einen Hydroxy-, Trifluormethyl- oder Nitrorest darstellen, verwendet.
  3. Verfahren gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, daß man zu Beginn ein Produkt der Formel (II), in der einer der drei Substituenten R₁ oder R₂ oder R₃ in Stellung 10 oder 11 einen Methyl-, Ethyl-, Methoxy- oder Ethoxyrest, ein Chloratom, einen Hydroxy-, Trifluormethyl- oder Nitrorest darstellt, wobei die beiden anderen Substituenten ein Wasserstoffatom darstellen, verwendet.
  4. Verfahren gemäß irgendeinem der Ansprüche 1 oder 2, dadurch gekennzeichnet, daß man zu Beginn ein Produkt der Formel (II), in der zwei der drei Substituenten R₁, R₂ oder R₃ in Stellung 9, 10 oder 11 ein Chloratom, einen Methyl-, Ethyl-, Methoxy- oder Ethoxyrest darstellen, wobei der dritte Substituent ein Wasserstoffatom darstellt, oder dadurch, daß R₁, R₂ und R₃ alle drei in diesen Stellungen ein Chloratom oder einen Methyl-, Ethyl-, Methoxy- oder Ethoxyrest darstellen, verwendet.
  5. Verfahren gemäß irgendeinem der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß man zu Beginn ein Produkt der Formel (II), in der das Wasserstoffatom in Stellung 3 und das Wasserstoffatom in Stellung 16 trans stehen, verwendet.
  6. Verfahren nach irgendeinem der Ansprüche 1 bis 5, dadurch gekennzeichnet, daß man ein Produkt der Formel (II) der Einwirkung eines geeigneten Reduktionsmittels unterzieht, um ein Produkt zu erhalten, welches der Formel (I) entspricht, in der
    Figure imgb0236
     für
    Figure imgb0237
     steht,
    welches man gegebenenfalls der Einwirkung eines geeigneten Dehydratisierungsmittels unterwirft, um ein Produkt zu erhalten, welches der Formel (I) entspricht, in der
    Figure imgb0238
     für
    Figure imgb0239
     steht.
  7. Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, daß man irgendeines der Produkte, deren Namen folgen:
    [(+)(14alpha,16alpha)]-14,15-Dihydro-10-methoxy-20,21-dinoreburnamenin-14-ol,
    [(±)(14alpha,16alpha)]-14,15-Dihydro-11-methyl-20,21-dinoreburnamenin-14-ol,
    [(±)(16alpha)]-11-Chlor-20,21-dinoreburnamenin,
    [(±)(16alpha)]-11-Methoxy-20,21-dinoreburnamenin,
    [(±)(16alpha)]-11-Methyl-20,21-dinoreburnamenin,
    sowie deren Additionssalze mit Mineral- oder organischen Säuren herstellt.
  8. Verfahren zur Herstellung von pharmazeutischen Zusammensetzungen, dadurch gekennzeichnet, daß man als Wirkstoff mindestens eine der wie in Anspruch 1 definierten Verbindungen der Formel (I) oder mindestens eines der pharmazeutisch annehmbarer Salze derselben in eine für diese Verwendung bestimmte Form bringt.
  9. Verfahren nach Anspruch 8, dadurch gekennzeichnet, daß die Verbindung der Formel (I) ausgewählt ist aus den Produkten, deren Namen folgen:
    [(+)(14alpha,16alpha)]-14,15-Dihydro-10-methoxy-20,21-dinoreburnamenin-14-ol,
    [(±)(14alpha,16alpha)]-14,15-Dihydro-11-methyl-20,21-dinoreburnamenin-14-ol,
    [(±)(16alpha)]-11-Chlor-20,21-dinoreburnamenin,
    [(±)(16alpha)]-11-Methoxy-20,21-dinoreburnamenin,
    [(±)(16alpha)]-11-Methyl-20,21-dinoreburnamenin,
    sowie deren Additionssalzen mit Mineral- oder organischen Säuren.
  10. Produkte der Formel (II), wie in Anspruch 1 definiert, mit Ausnahme der Produkte der Formel (IIA):
    Figure imgb0240
     für die R und R', die gleich oder verschieden sein können, einen Hydroxy- oder Methoxyrest darstellen.
EP88402872A 1987-11-19 1988-11-16 Substituierte Derivate von 20,21-Dinoreburnamenin, Verfahren zur Herstellung und so hergestellte Zwischenprodukte, ihre Verwendung als Arzneimittel und diese enthaltende pharmazeutische Zusammenstellungen Expired - Lifetime EP0317427B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT88402872T ATE100102T1 (de) 1987-11-19 1988-11-16 Substituierte derivate von 20,21dinoreburnamenin, verfahren zur herstellung und so hergestellte zwischenprodukte, ihre verwendung als arzneimittel und diese enthaltende pharmazeutische zusammenstellungen.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8715980 1987-11-19
FR8715980A FR2623501B1 (fr) 1987-11-19 1987-11-19 Nouveaux derives substitues de 20,21-dinoreburnamenine, leur procede de preparation et les nouveaux intermediaires ainsi obtenus, leur application comme medicaments et les compositions pharmaceutiques les renfermant

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EP0317427A1 EP0317427A1 (de) 1989-05-24
EP0317427B1 true EP0317427B1 (de) 1994-01-12

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US (2) US5093337A (de)
EP (1) EP0317427B1 (de)
JP (1) JP2694553B2 (de)
KR (1) KR970005299B1 (de)
AT (1) ATE100102T1 (de)
AU (1) AU621074B2 (de)
CA (1) CA1332735C (de)
DE (1) DE3887102T2 (de)
ES (1) ES2061712T3 (de)
FR (1) FR2623501B1 (de)
HU (2) HU204824B (de)
PT (1) PT89029B (de)
RU (1) RU2043353C1 (de)
UA (1) UA26443A (de)
WO (1) WO1989004830A1 (de)
ZA (1) ZA888663B (de)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2653124B1 (fr) * 1989-10-17 1992-01-17 Roussel Uclaf Nouveaux derives substitues en 15 de la 20, 21-dinoreburnamenine, leur procede de preparation et les nouveaux intermediaires ainsi obtenus, leur application comme medicaments et les compositions les renfermant.
CA2036337C (fr) * 1990-02-15 2003-04-15 Francois Clemence Derives de la 20,21-dinoreburnamenine, leur procede de preparation et les nouveaux intermediaires ainsi obtenus, leur application comme medicaments et les compositions les renfermant
FR2731154B1 (fr) * 1995-03-03 1997-05-09 Roussel Uclaf Compositions pharmaceutiques comprenant des derives de dinoreburnamenine
FR2865650B1 (fr) * 2004-01-30 2008-06-13 Biocortech Utilisation du 14,15 dihydro 20,21-dinoreburnamenin14-ol pour traiter et/ou prevenir les depressions majeures et les desordres du cycle veille-sommeil
FR2865649A1 (fr) * 2004-01-30 2005-08-05 Biocortech Utilisation du 14,15-dihydro 20,21-dinoreburnamenin14-ol pour traiter et/ou prevenir les depressions majeures
FR2869034B1 (fr) * 2004-04-14 2008-04-04 Biocortech Soc Par Actions Sim Derive du 14,15-dihydro 20,21-dinoreburnamenin 14-ol et leur utilisation pour le traitement des depressions

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2081587B1 (de) * 1970-03-26 1973-04-06 Anvar
DE2538095A1 (de) * 1974-09-06 1976-03-25 Sandoz Ag Neue organische verbindungen, ihre herstellung und verwendung
FR2339618A1 (fr) * 1976-01-30 1977-08-26 Omnium Chimique Sa Procede de preparation de (-)11-aminovincamone, de 11-aminoeburamonine, de 11-aminovincamone racemique et derives indoliques nouveaux
DE2703920A1 (de) * 1976-02-05 1977-08-11 Sandoz Ag Neue organische verbindungen, ihre herstellung und verwendung
FR2381048A1 (fr) * 1977-02-22 1978-09-15 Roussel Uclaf Nouveaux derives de 20,21-dinoreburnamenine, un procede pour leur preparation et leur application comme medicaments
HU180929B (en) * 1979-08-13 1983-05-30 Richter Gedeon Vegyeszet Process for producing new bromo-vincamone derivatives
HU183594B (en) * 1981-09-30 1984-05-28 Richter Gedeon Vegyeszet Process for producing 11-methoxy-vincamone
FR2514357A1 (fr) * 1981-10-08 1983-04-15 Roussel Uclaf Nouveaux derives de 20,21-dinoreburnamenine eventuellement substitues sur le cycle e, procede de preparation et application comme medicaments
HU191403B (en) * 1984-04-02 1987-02-27 Richter Gedeon Vegyeszeti Gyar Rt,Hu Process for preparing new, raceme and optically active 14-hydroxyimino-eburnane
HU191694B (en) * 1984-07-11 1987-03-30 Richter Gedeon Vegyeszet Process for production of new derivatives of amineburnan carbonic acid
HU198207B (en) * 1985-04-19 1989-08-28 Richter Gedeon Vegyeszet Process for production of derivatives of eburnamenin and medical compositions containing them
ES8604957A1 (es) * 1985-11-28 1986-03-16 Covex Sa Procedimiento para la preparacion del (+n-) 14,15-dihidro- (3b,14x,16x)-20,21-dinoreburnamenin-14-ol
FR2623503B1 (de) * 1987-11-19 1991-04-05 Roussel Uclaf

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HU886767D0 (en) 1990-09-28
AU621074B2 (en) 1992-03-05
KR970005299B1 (ko) 1997-04-15
DE3887102D1 (de) 1994-02-24
ES2061712T3 (es) 1994-12-16
HU211589A9 (en) 1995-12-28
UA26443A (uk) 1999-08-30
FR2623501A1 (fr) 1989-05-26
KR890701584A (ko) 1989-12-21
CA1332735C (fr) 1994-10-25
JP2694553B2 (ja) 1997-12-24
RU2043353C1 (ru) 1995-09-10
PT89029A (pt) 1988-12-01
US5093337A (en) 1992-03-03
ATE100102T1 (de) 1994-01-15
FR2623501B1 (fr) 1990-03-16
HUT53103A (en) 1990-09-28
JPH02502187A (ja) 1990-07-19
PT89029B (pt) 1993-02-26
HU204824B (en) 1992-02-28
AU2729588A (en) 1989-06-14
US5332748A (en) 1994-07-26
EP0317427A1 (de) 1989-05-24
WO1989004830A1 (fr) 1989-06-01
DE3887102T2 (de) 1994-05-05
ZA888663B (en) 1990-01-31

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